Clinical

Pharmacogenomics:

Applications to Clinical Care

May 19, 2018

Amber L. Beitelshees, PharmD, MPH

University of Maryland, Baltimore

School of Medicine

Objectives

Describe the current state of pharmacogenomics in clinical practice

Compare and contrast preemptive and reactive pharmacogenomics testing in clinical practice

Discuss the role of pharmacists in the clinical implementation of pharmacogenomics

One Drug Does NOT Fit All

http://www.personalizedmedicinecoalition.org/Userfiles/PMC-

Corporate/file/pmc_case_for_personalized_medicine.pdf

The Era of Precision

Medicine Also known as Personalized Medicine

Purpose: Provide the “right patient with the

right drug at the right dose at the right

time.”

Tailor medical treatment to the individual

characteristics, needs, and preferences of a

patient.

Identify genetic or protein biomarkers that

predict drug response and/or adverse effects.

Subset of personalized and

precision medicine.

Goal: Understand how

genetic variation contributes

to variability in drug

pharmacokinetics,

pharmacodynamics, and

toxicity.

Use genetic information to

guide optimal drug selection

and dosing to maximize

efficacy and minimize adverse

effects.

Pharmacogenomics (PGx)

Pharmacogenetics versus

Pharmacogenomics

Pharmacogenetics: Study of the relationship between variations in a single gene and variability in drug disposition, response, and toxicity.

Pharmacogenomics: Study of the relationship between variations in a large collection of genes (up to the whole genome) and variability in drug disposition, response, and toxicity

Ann Intern Med. 2006; 145:749-757

Managing Expectations

Relling and Evans; Nature 2015;526:343.

Actionable Genotypes in Individual and

Cumulative Drug-Gene Interactions

Van Driest et al. CPT 2014;95:423.

Clinical Pharmacogenetics

Implementation Consortium (CPIC)

Established in 2009 as a shared project between PharmGKB and

the Pharmacogenomics Research Network (PGRN).

Address the need for guidelines to instruct clinicians on how to

modify drug therapy based on genetic information.

Provide peer-reviewed, evidence-based clinical guidelines for

certain gene-drug pairs. Updated every two years.

CPIC guidelines are designed to help clinicians understand HOW

available genetic test results should be used to optimize drug

therapy.

Key assumption: Clinical high-throughput and pre-emptive

genotyping will become more widespread.

9

https://cpicpgx.org/

CPIC Guidelines/Updates

Other Evidence-Based

Resources

FDA Biomarker List

Information can be interpreted as genetic testing required,

recommended, actionable, or informative.

Dutch Pharmacogenetics Working Group (DPWG)

Professional society guidelines for certain gene-drug pairs.

Examples:

Canadian Pharmacogenomics Network for Drug Safety (e.g.,

carbamazepine)

DHHS antiretroviral guidelines (abacavir)

American College of Rheumatology (allopurinol)

Clinical Genome Resource (ClinGen)

Genetics and Genomics Competency Center (G2C2)

11

Case Presentations

Life-threatening sepsis due to leukopenia arises in a 9-year-old

girl after 6-MP therapy for ALL

A 32 year old male develops severe hypersensitivity reaction

to abacavir for treatment of HIV

A 55 year old woman started on simvastatin 40 mg/day shows

no decrease in LDL 1 month later and develops severe

myopathy rendering her wheel-chair bound

54 yr old male with lateral ST segment elevation MI presents

again 2 weeks later with stent thrombosis

Parent Drug

(Active)

Metabolite

(Inactive)

Parent Drug

(Active)

Metabolite

(Inactive)

Decreased metabolism due to genetic variant(s)

Increased plasma exposure of the active parent drug

Increased pharmacologic effect and/or risk of toxicity

Active Parent Drug

Increased metabolism due to genetic variant(s)

Decreased plasma exposure of the active parent drug

Decreased pharmacologic effect

Decreased

metabolism due

to genetic

variant(s)

Increased

metabolism due

to genetic

variant(s)

Prodrug

(Inactive)

Metabolite

(Active)

Prodrug

(Inactive)

Metabolite

(Active)

Decreased metabolism due to genetic variant(s)

Decreased plasma exposure of the active metabolite

Decreased pharmacologic effect

What about a Prodrug?

Increased metabolism due to genetic variant(s)

Increased plasma exposure of the active metabolite

Increased pharmacologic effect and/or risk of toxicity

Decreased

metabolism due

to genetic

variant(s)

Increased

metabolism due

to genetic

variant(s)

TPMT and Thiopurine Toxicity

Case: 9 yo girl with acute lymphoblastic

leukemia is initiated on mercaptopurine 75

mg/m2/day for maintenance therapy

2 weeks after starting therapy she develops

severe myelosuppression (leukopenia,

neutropenia, and thrombocytopenia)

Subsequently she develops an infection that

progresses to sepsis

She survives the episode but her

chemotherapy treatment has to be delayed

CASE 1:

Thiopurines (e.g. mercaptopurine, azathioprine, and

thioguanine)

Inhibit purine synthesis (antimitotic)

Immunosuppresants used for the treatment of

leukemia, inflammatory bowel disease, and other

immune function disorders

Rarely individuals have extreme sensitivity to

thiopurines

Increased risk for life-threatening

bone marrow suppression (leukopenia,

infection, anemia), hair loss, stomach

pain, diarrhea

Thiopurines are Inactivated

by TPMT

cytotoxic

6-thioguanines (6-TGNs)

HPRT = hypoxanthine-guanine phosphoribosyltransferase

TPMT = thiopurine S-methyltransferase

AZA

Therefore, there is

an inverse

relationship between

TPMT activity and

TGN concentration

(risk of toxicity)

TPMT Activity is Inherited

TPMT activity is inherited as a

monogenic co-dominant trait

3 SNPs account for >90% of

inactivating alleles

Phenotyping laboratory tests also

available

“Single Nucleotide

Polymorphisms” (SNPs)

TPMT Phenotypes

*3A/*3A

*1/*3A *1/*16-TGN concentrations

LL

*3A/*3A

(mutant)

HL

*1/*3A

(heterozygote)

HH

*1/*1

(wild-type)

1/300

[6-T

GN

]T

GN

co

nc

3-14% of pts 86-97% of pts1 in 178 - 1 in

3,736

10-fold dose

reduction

30-70%

dose

reduction

Standard

dose

Dosing recommendations in

Package Insert and in CPIC

guidelines

Abacavir is an HIV nucleoside analogue

Approximately 5% of treated patients develop

hypersensitivity syndrome [HSR] usually within 6 wks

Symptoms are: skin rash, gastrointestinal and respiratory

manifestations, re-challenge shock

Treatment is to stop the drug early; Re-treatment with

abacavir can cause severe allergic responses including

anaphylactic shock

Questioned whether hypersensitivity might be genetically

linked, and thus predictable

MHC proteins investigated b/c of known links in other

immune responses

Abacavir Hypersensitivity

Lancet 2002;359:727-32.

A 32 year old male develops severe hypersensitivity reaction to

abacavir for treatment of HIV

CASE 2:

PREDICT- I : Abacavir Pgx

Randomized Controlled Trial

ABC-naïve

Subjects

N=~1800

• 6-Week Observation

Period (covers 94% of

HSR cases)

ABC-containing regimen

HSR monitoring according to

Standard of Care

plus HLA-B*5701 screening

ABC-containing regimen

HSR monitoring according to

Standard of Care

Randomize (1:1) Exclude Subjects

with positive

screens

Enroll Subjects

with negative

screens

Mallal S. New Engl J Med 2008;358:568.

0

1

2

3

4

5

6

7

8

9

Incid

en

ce (

%)

3.4%

(27/803)

7.8%

(66/847)2.7%

(23/842)

OR 0.40

P < 0.0001

OR 0.03

P < 0.0001

Control arm

Prospective HLA-B*5701

screening arm

Clinically Suspected

HSRImmunologically Confirmed

HSR

PREDICT- I Results

0.0%

(0/802)

(0.25, 0.62)

(0, 0.18)

Mallal S. New Engl J Med 2008;358:568.

HLA Region and ADRs

Abacavir- hypersensitivity reaction

Flucloxacillin- DILI

Carbamazepine- Stevens-Johnson

syndrome

Ximelagatran- DILI

Amoxicillin-clavulanate- DILI

Allopurinol- Stevens-Johnson

syndrome

Genome-wide Association Studies

(GWAS):

Process of identifying novel

susceptibility genes for complex

diseases and traits can also be

applied to pharmacogenomics

Statin-Induced Myopathy

HMG CoA Reductase inhibitors

(statins) are used to lower cholesterol

Generally well tolerated, but rarely

associated with muscle pain/weakness

associated with elevated CK

Incidence typically 1 in 1,000 at doses

of 20-40 mg but increases with

increased doses and certain drugs

CASE 3:

A 55 year old woman started on simvastatin 40 mg/day

shows no decrease in LDL 1 month later and develops severe myopathy rendering her wheel-chair bound

GWAS – Simvastatin-induced Myopathy(NEJM; Aug 21, 2008)

SLCO1B1

SLCO1B1 Encodes the organic anion–

transporting polypeptide OATP1B1

Mediates the hepatic uptake of various drugs, including most statins

Rs4363657 in complete LD with functional rs4149056 (*5; V174A)

C allele associated with increased statin concentrations and increased risk of myopathy

Interestingly, C allele also associated with diminished LDL response

GWAS – Simvastatin-induced Myopathy(NEJM; Aug 21, 2008)

Population genotype

frequencies

TT = 73%

CT = 24.9%

CC = 2.1%

Myopathy cumulative risk 18% in C/Cs,

3% in C/Ts, and 0.6% in T/Ts.

Population attributable risk of 60%

My Results

Gene Diplotype

Summary

Flag

Relevant

Alleles Common Name

Re

fer

en

ce

Ba

se

Va

ria

nt

Ba

se Genotype Call

Change for

Variant cDNA change

dbSNP

rsnumber

SLCO1B1 *1a/*1b *17 *17,*21 SLCO1B1*17_c.-11187G>A(Promoter) G A G/G Ref/Ref Promoter -11187G>A rs4149015

SLCO1B1 *1a/*1b *2 *2,*12 SLCO1B1*2_c.217T>C(F73L) T C T/T Ref/Ref F73L 217T>C rs56101265

SLCO1B1 *1a/*1b V82A *3,*13 SLCO1B1_c.245T>C(V82A) T C T/T Ref/Ref V82A 245T>C rs56061388

SLCO1B1 *1a/*1b N130D

*1b,*14,*15,*

17,*18,*21 SLCO1B1*1B_c.388A>G(N130D) A G A/G Ref/Var N130D 388A>G rs2306283

SLCO1B1 *1a/*1b *16 *16 SLCO1B1*16_c.452A>G(N151S) A G A/A Ref/Ref N151S 452A>G rs2306282

SLCO1B1 *1a/*1b *4 *4,*14,*18 SLCO1B1*4_c.463C>A(P155T) C A C/C Ref/Ref P155T 463C>A rs11045819

SLCO1B1 *1a/*1b *3 *3,*13 SLCO1B1*3_c.467A>G(E156G) A G A/A Ref/Ref E156G 467A>G rs72559745

SLCO1B1 *1a/*1b *5 *5,*15,*17 SLCO1B1*5_c.521T>C(V174A) T C T/T Ref/Ref V174A 521T>C rs4149056

SLCO1B1 *1a/*1b *18 *18 SLCO1B1*18_c.578T>G(L193R) T G T/T Ref/Ref L193R 578T>G rs72559746

SLCO1B1 *1a/*1b *6 *6 SLCO1B1*6_c.1058T>C(I353T) T C T/T Ref/Ref I353T 1058T>C rs55901008

SLCO1B1 *1a/*1b *7 *7 SLCO1B1*7_c.1294A>G(N432D) A G A/A Ref/Ref N432D 1294A>G rs56387224

SLCO1B1 *1a/*1b *8 *8 SLCO1B1*8_c.1385A>G(D462G) A G A/A Ref/Ref D462G 1385A>G rs72559748

SLCO1B1 *1a/*1b *9 *9 SLCO1B1*9_c.1463G>C(G488A) G C G/G Ref/Ref G488A 1463G>C rs59502379

SLCO1B1 *1a/*1b *10 *10,*12 SLCO1B1*10_c.1964A>G(D655G) A G A/A Ref/Ref D655G 1964A>G rs56199088

SLCO1B1 *1a/*1b *11 *11,*13 SLCO1B1*11_c.2000A>G(E667G) A G A/A Ref/Ref E667G 2000A>G rs55737008

SLCO1B1 *1a/*1b N SLCO1B1_c.571T>C(L191L) T C T/C Ref/Var L191L 571T>C rs4149057

SLCO1B1 *1a/*1b N SLCO1B1_c.597C>T(F199F) C T C/T Ref/Var F199F 597C>T rs2291075

SLCO1B1 *1a/*1b P336R P336R SLCO1B1_c.1007C>G(P336R) C G C/C Ref/Ref P336R 1007C>G rs72559747

Simvastatin Dosing

Recommendations Rs4149056 T/T (*1/*1): Normal myopathy risk;

prescribe desired starting dose and monitor as

usual

Rs4149056 T/C (*1/*5, *1/*15, *1/*17):

Intermediate myopathy risk; prescribe lower

dose or consider alternate statin (eg

pravastatin or rosuvastatin); routine CK

surveillance

Rs4149056 C/C (*5/*5, *5/*17, *17/*17, *15/*15,

*5/*15, *15/*17): High myopathy risk; prescribe

lower dose or alt statin; routine CK surveillanceCPIC Guidelines

Anti-platelet agent

Effective (with aspirin) for prevention of MI and

stroke, and thrombosis prevention coronary stent

placement and angioplasty

In 2011, world’s 2nd highest selling drug

U.S. sales $6.7 billion

Acts by binding to ADP receptors on platelets,

preventing platelet aggregation and thrombosis

Great variability in response to clopidogrel

4 - 32% of individuals are resistant

Clopidogrel54 yr old male with lateral ST segment elevation MI presents

again 2 weeks later with stent thrombosis

CASE 4

The Amish Pharmacogenomics of Antiplatelet

Intervention (PAPI ) Study

600 healthy Amish individuals

Treated with clopidogrel for 7 days; aspirin added on day 7

Platelet aggregation studies pre-clopidogrel, post-clopidogrel, and post-clopidogrel plus aspirin

Distribution of

clopidogrel

response

Clopidogrel works in

the population but not

in all individuals

Heritability of clopidogrel

response = 0.7

GWAS with Affy 500k

array

Genome-wide

Association Study of

Clopidogrel

Response(ADP-stimulated platelet

aggregation after

clopidogrel treatment)

Shuldiner et al JAMA 2009;302:849

CYP2C19*2 Loss of Function Variant Is a Major

Determinant of Clopidogrel Response

CYP2C19 genotype accounts for 12% of the variation in

clopidogrel response

33%

Shuldiner et al JAMA 2009;302:849

Event-Free Survival in Patients Treated With Clopidogrel Following PCI Stratified by CYP2C19*2 Genotype

Shuldiner et al JAMA 2009;302:849

CYP2C19 Genotyping in the

“Real-World”

Cavallari LH, et al. JACC Cardiovasc Interv 2018;11(2):181.

Types of PGx Testing Targeted, reactive testing (“Just-in-Time”):

Conduct pertinent genetic testing as a medication

is prescribed.

Disadvantages: Delay in obtaining results; Cost.

Pre-emptive testing (“Just-in-Case”): Conduct

genetic testing on many pharmacogenes at one

time and store the information electronically for

future use.

Disadvantages: EMR capable of securely housing and

disseminating information; Clinical decision support.

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What is the Pharmacist’s Role?

ASHP Statement on the Pharmacist's Role in Clinical

Pharmacogenomics

“Pharmacists…have a fundamental responsibility to ensure

that pharmacogenomic testing is performed when needed

and that results are used to optimize medication therapy.”

“…all pharmacists should have a basic understanding of

pharmacogenomics in order to provide appropriate patient-

care recommendations.”

“ASHP…advocates inclusion of pharmacogenomics and its

application to the therapeutic decision-making process in

college of pharmacy curricula…”

Am J Health Syst Pharm 2015;72(7):579-81

ASHP Statement on the Pharmacist's

Role in Clinical Pharmacogenomics

Elements of a basic understanding of

pharmacogenomics should enable

pharmacists to: Recommend PGx testing to aid in drug and dose selection.

Design a patient-specific medication regimen based on a

patient’s PGx profile.

Educate patients and other health care providers on the

principles of PGx and indications for testing.

Communicate PGx-specific medication recommendations to

the health care team.

Am J Health Syst Pharm 2015;72(7):579-81

Resources

PharmGKB

http://www.pharmgkb.org/index.jsp

CPIC

www.cpicpgx.org

IGNITE- SPARK toolbox

https://ignite-genomics.org/spark-toolbox/

Genetics and Genomics Competency

Center (G2C2)

https://genomicseducation.net